Staphylococcus aureus elongation factor G - structure and analysis of a target for fusidic acid
Staphylococcus aureus elongation factor G - structure and analysis of a target for fusidic acid
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DOI：
10.1111/j.1742-4658.2010.07780.x
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发表时间：
2010-09-01
期刊：
影响因子：
5.4
通讯作者：
Selmer, Maria
中科院分区：
文献类型：
--
作者：
Chen, Yang;Koripella, Ravi Kiran;Selmer, Maria
福西地酸（FA）是一种抑菌抗生素，在易位后锁定核糖体上的延伸因子G （EF-G）。它在临床上用于治疗革兰氏阳性细菌，如金黄色葡萄球菌的致病菌株，但尚未获得这些物种的EF-G的结构信息。我们对金黄色葡萄球菌EF-G的载子晶体结构进行了1.9 A分辨率的解析。这种结构显示出与以前的EF-G结构显著不同的整体构象，尽管个别结构域高度相似。在游离或核糖体结合的EF-G的不同结构之间，结构域III-V相对于结构域I-II移动，导致结构域IV的尖端相对于结构域g发生位移。在金黄色葡萄球菌EF-G中，这种位移相对于嗜热菌EF-G的结构在垂直于先前观察的方向上约为25 a。部分开关I区（残基46-56）呈螺旋状排列，与GDP和GTP状态下的EF-Tu结构相比具有不同的构象。此外，开关II区显示出一种新的构象，与游离EF-G的其他结构一样，与FA结合不相容。根据金黄色葡萄球菌EF-G的新结构，以及嗜热葡萄球菌EF-G与70S核糖体与fususidic酸复合物的最新结构，我们分析和讨论了所有已知的fusasbased fususidic acid抗性突变[Gao YG et al. (2009) Science326, 694-699]。这些突变可分为影响FA结合、EF-G核糖体相互作用、EF-G构象和EF-G稳定性。
Fusidic acid (FA) is a bacteriostatic antibiotic that locks elongation factor G (EF-G) on the ribosome in a post-translocational state. It is used clinically against Gram-positive bacteria such as pathogenic strains of Staphylococcus aureus, but no structural information has been available for EF-G from these species. We have solved the apo crystal structure of EF-G from S. aureus to 1.9 A resolution. This structure shows a dramatically different overall conformation from previous structures of EF-G, although the individual domains are highly similar. Between the different structures of free or ribosome-bound EF-G, domains III-V move relative to domains I-II, resulting in a displacement of the tip of domain IV relative to domain G. In S. aureus EF-G, this displacement is about 25 A relative to structures of Thermus thermophilus EF-G in a direction perpendicular to that in previous observations. Part of the switch I region (residues 46-56) is ordered in a helix, and has a distinct conformation as compared with structures of EF-Tu in the GDP and GTP states. Also, the switch II region shows a new conformation, which, as in other structures of free EF-G, is incompatible with FA binding. We have analysed and discussed all known fusA-based fusidic acid resistance mutations in the light of the new structure of EF-G from S. aureus, and a recent structure of T. thermophilus EF-G in complex with the 70S ribosome with fusidic acid [Gao YG et al. (2009) Science326, 694-699]. The mutations can be classified as affecting FA binding, EF-G-ribosome interactions, EF-G conformation, and EF-G stability.